Adipose Tissue-Derived Stem Cells and the Importance of Animal

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Rev Bras Cardiol Invasiva.
2013;21(3):281-7
Original Article
Adipose Tissue-Derived Stem Cells and the Importance
of Animal Model Standardization for Pre-Clinical Trials
Marilia Sanches Santos Rizzo Zuttion1, Cristiane Valverde Wenceslau2,
Pedro A. Lemos3, Celso Takimura4, Irina Kerkis5
ABSTRACT
Stem cells are undifferentiated cells and can self-renew and
differentiate into various cell types, besides having immunomodulating properties and paracrine effects in response to
tissue injury, and may therefore treat injuries and diseases or
even replace damaged or lost cells. Adipose tissue is an attractive source of adult stem cells, since the human body has
a large reserve that is obtained in large amounts by minimally
invasive methods. Interest in these cells has been increasing
steadily due to their properties and possible applications in
regenerative medicine and cell therapy. A large part of these
investigations are focused on cardiovascular diseases, which
are a leading cause of morbidity and mortality worldwide.
Although in recent years treatments have advanced in cardiology, the development of new therapies to recover the
damaged tissue still remains one of the main goals of cardiac
research. However, to achieve effective results, in vivo and in
vitro animal models for preclinical studies and consequently
for application in humans must be standardized. The development of preclinical models in large animals requires the
use of well-characterized animal cell lines, similar to human
cells, and the use of the porcine model represents a great
advantage for preclinical translational research.
RESUMO
Células-Tronco de Tecido Adiposo e a Importância
da Padronização de um Modelo Animal para
Experimentação Pré-Clínica
As células-tronco são células indiferenciadas, capazes de se
autorrenovar e de se diferenciarem em diversos tipos celulares, além de apresentarem propriedades imunomoduladoras e
efeitos parácrinos mediante injúria tecidual, podendo, dessa
forma, tratar lesões e doeņas ou ainda substituir células
daniicadas ou perdidas. Dentre as fontes de células-tronco
adultas, o tecido adiposo é uma fonte atrativa, pois o organismo humano possui grande reserva desse tecido, que, por sua
vez, é obtido em grandes quantidades por meio de métodos
pouco invasivos. O interesse nessas células vem aumentando
constantemente devido a suas propriedades e posśveis aplica̧ões na medicina regenerativa e terapia celular. Grande parte
dessas pesquisas está voltada para doeņas cardiovasculares,
que são a principal causa de morbidade e mortalidade em
todo o mundo. Embora nos últimos anos, os tratamentos em
cardiologia tenham avaņado, o desenvolvimento de novas
terapias que recuperem o tecido daniicado ainda permanece
como um dos objetivos principais das pesquisas card́acas.
Porém, para obter resultados eicazes, é necessária a padroniza̧ão de modelos animais in vivo e in vitro para estudos
pré-cĺnicos e, consequentemente, a aplica̧ão em humanos.
O desenvolvimento de modelos pré-cĺnicos em animais de
grande porte exige o uso bem caracterizado de linhagens de
células animais semelhantes aos seus equivalentes humanos.
O modelo súno representa uma grande vantagem para a
investiga̧ão translacional pré-cĺnica.
DESCRIPTORS: Stem cells. Adipose tissue. Cardiovascular
diseases. Swine. Models, animal.
DESCRITORES: Células-tronco. Tecido adiposo. Doeņas cardiovasculares. Súnos. Modelos animais.
1
Postgraduate (Doctorare) at the Biology Department of Estrutural e
Funcional da Universidade Federal de São Paulo. São Paulo, SP, Brazil.
2
Postgraduate at the Structual and Funcional Biology Department of
Universidade Federal de São Paulo. São Paulo, SP, Brazil.
3
Full professor. Director of the Hemodynamics and Interventional
Cardiology Service of Instituto do Cora̧ão do Hospital das Cĺnicas
da Faculdade de Medicina da Universidade de São Paulo. São Paulo,
SP, Brazil.
4
Doctor. Researcher Physician at Instituto do Cora̧ão do Hospital das
Cĺnicas da Faculdade de Medicina da Universidade de São Paulo.
São Paulo, SP, Brazil.
Correspondence to: Irina Kerkis. Laboratório de Genética do Instituto
Butantan − Av. Vital Brasil, 1.500 − São Paulo, SP, Brazil − CEP 05503-900
E-mail: [email protected]
Received on: 3/28/2013 • Accepted on: 8/8/2013
Source offinancial support: Marilia Sanches Santos Rizzo Zuttion receives a grant from the Coordena̧ão de Aperfei̧oamento de Pessoal
de Ńvel Superior (CAPES).
© 2013 Sociedade Brasileira de Hemodinâmica e Cardiologia Intervencionista. Published by Elsevier Editora Ltda. All rights reserved.
282
Zuttion et al.
Stem Cells from Adipose Tissue
S
tem cells (SCs) are undifferentiated cells that can
self-renew and differentiate into many cell types. In
these processes of self-renewal and differentiation,
the SCs can undergo two different types of division:
(1) symmetrical division, in which the SC generates a
new SC cell and a progenitor cell, and (2) asymmetrical
division, in which the SC generates differentiated cells.1
This process occurs while maintaining tissue homeostasis
and the active SC niche. The niches are physiological
microenvironments, consisting of specialized cells that
signal and provide molecules on the cell surface to
control the rate of proliferation of SCs, determining the
differentiation of progenitor cells and protecting SCs from
apoptosis. This reciprocal interaction between the SCs
and the niche occurs in the early stages of embryonic
development and is maintained during adulthood, and
is essential for ontogeny and tissue repair.2
SCs are divided into two main types, according to
their origin and plasticity. SCs may be of embryonic
origin, that is, are isolated from the zygote or the inner cell mass of the blastocyst, or they may be derived
from the adult organism. Concerning the capacity of
these cells to originate organism tissues, embryonic
stem cells (ESCs) are classiied as pluripotent, i.e., they
are capable of generating all body cell types; whereas
adult SCs (ASCs) have a more restricted differentiation
potential, and are classiied as multipotent.
ASCs were irst described by Friendestein in 1970,
who isolated in vitro stromal cells from bone marrow of
mice. In that study, he demonstrated the morphological
characteristics of cell expansion and differentiation. 3
Subsequently, in different culture conditions, it was
observed that bone marrow ASCs were able to differentiate into osteoblasts, chondrocytes, and adipocytes.4
Based on this capacity to differentiate into different cell
types, Caplan proposed in 1991 the term “mesenchymal
stem cell” (MSC).5
The most studied source of MSCs is the bone marrow. MSCs from bone marrow, which represent a rare
subpopulation (< 0.01% of the mononuclear cells from
bone marrow) are a group of clonogenic cells, found in
the bone marrow stroma and capable of differentiating
not only into cells of mesodermal origin, but also into
other non-mesodermal cell types, such as the neural
and the hepatocytes.6
ASCs are known as multipotent, and differently
from what was originally believed, they are not involved only in the process of repair and homeostasis
in tissues from which they are isolated, but also have
several paracrine effects that contribute to the recovery
and regeneration of other cell types and tissues in the
body,7 as these cells produce and secrete a variety of
cytokines, chemokines, and growth factors, which act
in a paracrine manner in in vivo tissue regeneration.8
2013;21(3):281-7
CELL CHARACTERIZATION
For a cell population to be considered SCs, it
must meet at least three requirements according to the
International Society for Cellular Therapy:
1. They have to be plastic-adherent, while maintained in culture conditions;
2. They have to be positive for CD105, CD73, and
CD90, and negative for CD45, CD34, CD14, CD11b,
CD79, or CD19 and HLA-DR.9 However, depending on
the source from which they are obtained, the methods
of cell isolation, and characteristics of the culture, the
expression of these markers can occur differently. ASCs
can also express other surface proteins such as CD44,
CD71 (transferrin receptor), Stro-1 and ibronectin,
vimentin, and CD73 (ecto-5’-nucleotidase, SH3, and
SH4), among others.10,11 More studies are still needed
to elucidate the expression variability of severalmarkers;
3. They have to be capable of differentiating into
osteoblasts, chondrocytes, and adipocytes.9
MSC SOURCES
As previously stated, the bone marrow is the most
common source of MSCs,12 but similar populations have
also been obtained from other sources, such as umbilical cord blood, placenta, amniotic luid, dermis, liver,
spleen, dental pulp,14 and adipose tissue.15
Among these sources, the adipose tissue stands
out, which offers more advantages compared to other
sources, due to its low risk for donors, higher number
of MSCs (it is possible to collect 100 mL from 1 L of
adipose tissue), and capability of maintaining their proliferative potential for eight to ten passages without any
detectable deterioration in their capacity of self-renewal,
in addition to the absence of immunologic rejection.16
THE ADIPOSE TISSUE
Adipose tissue has mesodermal origin and contains
a heterogeneous stromal cell population. The mesoderm
arises during gastrulation as a medial layer between
the endoderm and ectoderm. The embryonic mesoderm
gives origin to several types of muscles – including the
heart, all connective tissue, blood vessels, blood cells,
and lymphatic vessels. 15 Historically, adipose tissue
was considered a metabolic reservoir for storage and
release of energy substrates in the form of triglycerides
and cholesterol, as well as fat-soluble vitamins. In the
mid-1980s, this concept was modiied, based on the
identiication of its role in sexual physiology through
sexual steroids.17 The adipose tissue is a component
of connective tissue with important functions, such as
providing rigidity and resistance to tissues, maintaining
thermal homeostasis, and assisting in visceral static. In
Zuttion et al.
2013;21(3):281-7
mammals, the predominant type of adipose tissue is the
white type, compared to brown adipose tissue, which
is found in neonates, but is virtually absent in adults.18
This tissue is distributed in the body as subcutaneous
white adipose tissue and white visceral adipose tissue,
consisting of mature adipocytes, preadipocytes, ibroblasts, smooth muscle vascular cells, endothelial cells,
resident monocytes, and macrophages and lymphocytes.19
According to Zannetino et al.,2 the niche of MSCs
in adipose tissue is located in the perivascular region,
and consists of blood vessels in association with connective tissue, adipose stromal tissue, and many progenitor cells and SCs (Figure 1). It may be stated that
the adipose tissue SC niche is perivascular. Although
the term “perivascular” means “around blood vessels”,
adipose tissue SCs are also found within the vessels, as
a part of the blood vessel wall components. However,
due to the lack of speciic markers, the exact location
and cell identity are still elusive.
The vascular network plays a role in adipogenesis.
During embryonic development, the formation of capillaries is a decisive and speciic phase in the development
of adipose lobules, and an adequate vascularization is
required for optimal functioning of the adipose tissue
as a metabolic and endocrine organ. In addition, the
adipogenic lineage cells secrete potent angiogenic factors, such as monobutyrin, vascular endothelial growth
factor, leptin, and adiponectin. Finally, anti-angiogenic
factors promote the loss of adipose tissue, thereby
demonstrating the importance of angiogenesis for the
maintenance of adipogenesis.20-22 However, large quantities of SCs can be isolated from this vascular fraction
through the enzymatic digestion method.
Adipose Tissue
Progenitor cells Stromal Cells
Stem Cell
Cell nucleus
Cytoplasm
Blood
vessels
Adipose cells
283
ISOLATION OF MCS FROM ADIPOSE TISSUE
In 1964, Martin Rodbell23 established the in vitro
isolation method of mature adipocytes and adipogenic
progenitor cells from adipose tissue of rats. In his
protocol, the tissue was fragmented and digested with
type I collagenase enzyme at 37°C and the material
was then centrifuged. The supernatant contained mature
adipocytes and the pellet had components of vascular
stromal fraction, including adipocyte progenitor cells
and hematopoietic lineage cells.
As in many ields with a rapid development, a number of names have been used for describe the adherent
cell population, isolated from the enzymatic digestion
by collagenase from adipose tissue, such as lipoblast,
pericytes, pre-adipocyte, processed lipoaspirate, adipose
tissue-derived stromal SC, adipose tissue-derived ASC,
adipose tissue-derived stromal adult cell, adipose tissuederived multipotent SC, and adipose tissue MSC (Figure
2A to 2C). The International Fat Applied Technology
Society (IFATS) proposed a standardized nomenclature
in Pittsburgh in 2004, adopting the term ASC, or adipose stem cell, to refer to the population of adherent
multipotent cells isolated from the vascular stromal
fraction.24 The adipose tissue MSCs were isolated and
characterized in humans and in animal species.13,25-30
ADIPOSE TISSUE MSCS
Similarly to the bone marrow, the adipose tissue
MSCs have a broad differentiation potential in several
different cell types, such as adipogenic, chondrogenic,
osteogenic, (Figure 2D to 2F), myogenic, angiogenic,
neurogenic, myogenic and cardiomiogenic.31 Nevertheless,
the isolation success rate is 100% and the adipose tissue
yield is 40 times higher than that of bone marrow.32
Furthermore, the quantity of cells does not appear to
decrease with age, making this type of cell attractive
for the isolation of MSCs and progenitor cells.33
The MSCs have the capacity to accumulate around
inlammatory processes when administered in vivo, due
to their chemotactic properties. Therefore, these cells
can be used in several areas, such as in regenerative
therapy.7 Currently, cells with characteristics similar
to those of human MSCs were isolated in vitro from
several animals (pigs,34-38 dogs,39 sheep40). These animals
are often used in regenerative medicine research as
animal models for osteoarticular diseases,41 spinal cord
injury,42 and myocardial infarction.37
REGENERATIVE MEDICINE
Fat globules
Connective tissue cells
Figure 1. Figure illustrating adipose tissue-derived adult stem cell niche.
Source: Irina Kerkis
As shown above, adipose-tissue SCs exhibit abundant
capacity of expansion in vitro and, more importantly,
can originate cells of different cell lineages and even
cardiomyocytes,32,43 in addition to the absence of ethical
284
Zuttion et al.
2013;21(3):281-7
A
B
D
E
C
F
Figure 2 – Swine adipose tissue-derived stem cells. (A) Isolation of stem cells from adipose tissue. (B) Morphology of adipose tissue-derived stem cells.
(C) Colony-forming unit assay in adipose tissue-derived stem cells. (D) Adipogenic differentiation. Note the cells with lipid droplets. (E) Osteogenic
differentiation (von Kossa staining); mineralization can be observed. (F) Hematoxylin-eosin staining demonstrating the chondrogenic differentiation.
Scale bars: A = 20 mm; B to F = 10 micrometers. A, B, and D = phase contrast. C, E, and F = optical microscopy. Source: Zuttion et al., 2013
(unpublished data).
questions regarding their use. Therefore, adipose tissue
has become a very attractive source of MSCs for regenerative medicine, and cardiology is one of the areas
in which these cells are very frequently employed.6
The leading cause of death worldwide due to non
communicable diseases is cardiovascular disease (48%),
such as myocardial infarction and congestive heart failure.44 Other diseases also cause myocardial dysfunction,
such as Chagas disease and other cardiomyopathies.45
Advances in the treatment of cardiovascular diseases are due, in part, from the development of coronary revascularization techniques, and pacemaker and
deibrillator implantation. With the exception of heart
transplantation, these treatment options are limited
by their incapacity to substitute lost cardiomyocytes
and myocardial scars, and this is aggravated by the
incapacity of the heart to replace its cell mass through
self-renewal. New treatment approaches are necessary;46 alternatively, SC therapy has been proposed
to generate new cardiomyocytes.47 Some studies have
demonstrated the capacity of adipose tissue and bone
marrow MSCs to differentiate into cardiomyocytes.48-50
However, some studies have shown that the differentiation of MSCs into cardiomyocytes, when injected into
the heart muscle, is arare event, demonstrating that the
MSCs are not capable of generating cardiomyocytes in
suficient amounts to repair myocardial injury.51 However, the MSCs have not only an autocrine, but also a
paracrine property, that is, when the MSCs are injected,
they secrete factors (vascular endothelial growth factor,
basic ibroblast growth factor, hepatocyte growth factor, insulin-like growth factor 1, and adrenomedullin),
which play an anti-apoptotic, pro-angiogenic role and
have an endogenous reparative effect, in addition to
exerting aparacrine action directly on cardiomyocytes,
increasing their rate of survival.52
Another important biological process influenced
by MSCs through their paracrine effects is neovascularization. Recent preclinical studies with femur
fractures in rats have demonstrated the angiogenic
potential of SCs derived from human adipose tissue.
After ASC transplantation, an increase of angiogenesis
2013;21(3):281-7
and neovascularization around the area of endochondral ossification occurred, as well as a significant
increase of capillary density.53 In another study using
pigs as an animal model, it was shown that eight
weeks after intramyocardial MSC transplantation,
there was improvement in left ventricular function.
The researchers observed that, after the first week of
transplantation, there was improvement in myocardial
blood flow during diastole, which was directly related
to blood vessel size increase. These results indicated
the process of neovascularization as a consequence
of significant cardiomyogenesis.54 This is due to the
production and secretion by MSCs of factors such as
nitric oxide, vascular endothelial growth factor, basic
fibroblast growth factor, angiopoietin, and hepatocyte
growth factors, among others. The action of these factors
leads to migration and proliferation of endothelial cells
and vascular smooth muscle cells, as well as increase
and maturation of vessels and extracellular matrix
synthesis. Thus, the MSCs would improve capillary
density and act in the formation of collateral vessels.7
However, despite much research on the differentiation
potential of these cells in cardiomyocytes, studies are
still necessary to understand these mechanisms.
ANIMAL MODEL USED IN SC RESEARCH
Since many years ago until the present day, several
species of animals have been used as experimental
subjects in scientiic research, aiming to discover prophylactic or treatment measures for many diseases.55,56
Around 1865, Claude Bernard57 started using animals as a study model for transposition of acquired
knowledge to understand human physiology. In his
study, Bernard57 sought physical and chemical changes
that caused alterations in animals similar to human
diseases. Small animals (mice, rats, hamsters, or gerbils) comprise more than 90% of the total species
used in laboratories,48 but the ideal model for use in
research would be the one that resembled the human
being in their physiological, anatomical, and organic
characteristics, which impacts the effectiveness of the
obtained conclusions.57
Given this fact, many results of studies with SCs
are inconclusive due to the practice of xenotransplantation (transplantation of organs or cells from different
species), because these cells are usually isolated from
human beings58,59 and transplanted to other species,
which complicates the study and understanding of
their action in the body. Furthermore, few animals are
similar to the human organism, which further reduces
the understanding of SCs. Thus, it would be ideal to
have an animal model that was similar to humans in
anatomy, physiology and pathophysiology. According to
Bustard and McClellan,60 the pig (Sus scrofa domesticus)
has similarities with humans regarding odontology, renal
Zuttion et al.
285
morphology and physiology, visual acuity, eye structure,
skin physiology and morphology, cardiovascular physiology and anatomy, digestive physiology and anatomy,
and immunology. These similarities are more distant in
other models, such as dogs, rats, mice, and other species
used in research.56 According to Tumbleson,61 pigs are
an effective model for studies in biomedical research
because, in addition to presenting structures and functions
similar to that of the human, it has similarity regarding
size, diet pattern, digestive physiology, dietary habits,
kidney structure and function, lung vascular structure,
distribution of coronary arteries, propensity for obesity,
respiratory frequency, and social behavior; and it is a
lexible animal model to determine the effects of acute
and chronic exposures to alcohol, caffeine, tobacco,
food additives, and environment pollutants.
Regarding adipose tissue MSCs, the pig model
would be ideal, because in addition to all the similarities
with human being, this animal has a large reserve of
adipose tissue,61 facilitating MSC isolation from adipose
tissue and autologous or heterologous transplantation
(transplantation of organs or cells to the same species),
in order to evaluate the mechanism of action of these
cells and human MSCs.
SWINE ADIPOSE TISSUE SCs
Several authors have performed the isolation of
adipose tissue-derived SC in pigs. Such cells showed
potential to differentiate into different mesodermal
lineages, such as bone, cartilage, fat, muscle, and
cardiomyocytes, and expressed different SC markers,
showing similarities with human adipose tissue-derived
MSCs.34-38 Interestingly, pigs are already widely used in
this ield regarding endovascular device implantation,
such as stents.62,63 However, it is a good preclinical
model to test the effect of SCs speciically in the area
of SCs applied to cardiovascular diseases.
Moreover, these cells isolated from pigs have been
partially characterized regarding the expression of MSC
markers, and therefore it is dificult to compare the
beneits of these cells in an organism not similar to
the human body.
FINAL CONSIDERATIONS
The MSCs isolated from adipose tissue have a wide
differentiation potential and can be easily obtained in
large quantities through minimally-invasive and low-pain
methods. Furthermore, these cells are able to promote
the immunomodulation of the immune system and have
a paracrine effect capable of mobilizing molecules to
regenerate injured tissue. However, much of the research
on SCs is limited, due to the use of xenotransplantation and the lack of standardization of animal models
that are anatomically and physiologically close to that
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Zuttion et al.
of the human body, for instance, pigs. Therefore, a
greater knowledge of the action mechanism of these
cells is necessary, in a physiological environment that
reproduces the human organism. This fact has caused
some clinical and therapeutic applications of SC to
remain uncertain. In summary, the expectation of regenerative medicine based on SC use depends on the
knowledge of the mechanism of these cells and their
effects on the body, as well as of the molecules, factors, and signalling cascades that control cell survival
and proliferation – through contact with SCs. Therefore,
the applicability of SCs depends mostly on the use of
suitable models and well characterized SCs. Multiple
solutions are likely to emerge from growing technologies
in the SC and regenerative medicine area. Numerous
innovations will change the practice of medicine through
the recognition that living cells are able to perform a
series of functions that drugs cannot provide.
CONFLICTS OF INTEREST
The authors declare no conlicts of interest.
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